This proposal builds on a longitudinal cohort study of persons participating in the Beaver Dam Eye Study (BDES), funded by National Eye Institute grant U10 EY006594. The study included persons aged 43-86 years living in the city and township of Beaver Dam, Wisconsin who were identified in a private census in 1987-88 and were examined in 1988-1990 and every 5 years thereafter. At each examination, age-related macular degeneration (AMD) and other retinal diseases were graded from stereoscopic fundus photography, and refraction and visual acuity were measured. This will be done at the 25 year follow-up. Spectral domain optical coherence tomography (SD-OCT), a noninvasive, quantitative method used to measure retinal thickness and to document other anatomic features not observed with fundus photography, and frequency doubling technology (FDT) perimetry were added at the 20-year follow-up. We will measure skin intrinsic fluorescence (SIF), serum advanced glycation endproducts (AGEs), a soluble receptor for AGEs (s-RAGE), and oxidized low-density lipoprotein cholesterol (ox-LDL), a marker of oxidative stress, at the proposed 25-year follow-up examination. In addition, we will measure AGEs and ox-LDL from frozen serum collected at previous examinations to determine their longitudinal associations to the incidence and progression of AMD over the 25 years of study, as well as how markers of inflammation, subclinical atherosclerosis and candidate genes may alter the associations. We will examine the utility of these measures for risk assessment of developing AMD. We will also examine the relationships of SIF with the prevalence and severity of AMD, the relationships of retinal morphology identified by SD-OCT and FDT perimetry to the 5-year incidence and progression of AMD as measured by color fundus photographs, and the longitudinal relationships of the aforementioned newly measured analytes to retinopathy and cataract. Discovering and describing retinal features that are harbingers of the development of the earliest lesions of AMD through SD-OCT will permit timely intervention to derail or prevent the development of AMD. The new data from this study will provide a unique opportunity to examine the role of nonenzymatic glycation and oxidative stress in the pathogenesis of AMD independent of age, smoking status, and high-risk genetic markers.